Understanding the cardiovascular risk in antihistamine-refractory chronic urticaria patients using biological agents
Imagine waking up each day not knowing what your skin will look like—whether angry red welts will appear without warning, bringing relentless itching that disrupts your sleep, work, and peace of mind. This is the reality for millions living with chronic spontaneous urticaria (CSU), an unpredictable skin condition characterized by recurring hives and swelling that persists for more than six weeks. For approximately 1% of the global population, this isn't just an occasional allergy but a daily battle 7 .
Approximately 1% of the world's population suffers from chronic spontaneous urticaria
Nearly half of CSU patients don't respond adequately to standard antihistamine treatment
The journey typically begins with antihistamines, the standard first-line defense. But for nearly half of patients, these medications provide insufficient relief, even at increased doses. These antihistamine-refractory cases represent a treatment challenge that has driven the development of advanced therapies, particularly biological agents that target specific immune pathways 2 5 .
Among these breakthroughs, omalizumab—a monoclonal antibody that neutralizes immunoglobulin E (IgE)—has revolutionized CSU management. But as researchers accumulated data on thousands of patients treated with this and other biologics, an important question emerged: could the underlying inflammatory processes that drive stubborn urticaria also affect cardiovascular health? Recent research has begun to uncover surprising connections that every patient and clinician should understand 1 .
Chronic spontaneous urticaria is far more than just "a skin problem." The condition represents a complex immune dysregulation where mast cells in the skin become activated, releasing histamine and other inflammatory mediators that cause wheals, intense itching, and sometimes angioedema (deeper tissue swelling) 7 .
Approximately 40-50% of CSU patients experience angioedema, while for about 10%, it becomes their primary symptom 7 . The "spontaneous" designation is crucial—it means symptoms occur without obvious triggers, unlike physical urticarias that respond to specific stimuli like pressure, cold, or heat.
The theory connecting CSU to cardiovascular risk stems from our growing understanding of systemic inflammation. When the body exists in a persistent state of immune activation—as occurs in CSU—the inflammatory mediators circulating throughout the bloodstream can gradually damage blood vessels and promote atherosclerosis (hardening of the arteries) 1 .
This pattern mirrors what physicians observe in other inflammatory conditions. Rheumatoid arthritis, psoriasis, and lupus all carry documented increased cardiovascular risks, suggesting that chronic inflammation itself may be an independent risk factor for heart disease 1 .
Persistent immune activation in CSU leads to elevated inflammatory mediators throughout the body
Inflammatory cytokines damage blood vessel lining, impairing vascular function
Chronic inflammation accelerates plaque buildup in arteries
Higher incidence of hypertension, metabolic syndrome, and potential for cardiac events
In 2024, researchers in Turkey designed a focused investigation to directly examine cardiovascular risk in antihistamine-refractory CSU patients. Their work, published in the journal Postepy Dermatologii Alergologicznej, represents one of the first dedicated attempts to quantify this potential connection in patients receiving biologic treatment 1 .
The research team employed a retrospective case-control methodology, comparing 85 patients with diagnosed CSU against 85 matched control subjects without urticaria. All CSU participants had confirmed antihistamine-refractory disease and were receiving biological agent treatment 1 .
The investigators used two established assessment tools to evaluate cardiovascular risk factors. The 10-year cardiovascular risk was calculated according to the Framingham Heart Study criteria, while metabolic syndrome was identified using the National Cholesterol Education Program Adult Treatment Panel III guidelines. This comprehensive approach allowed them to examine both immediate and longer-term cardiovascular health indicators 1 .
| Aspect | Description |
|---|---|
| Design | Retrospective case-control study |
| Participants | 85 CSU patients vs. 85 matched controls |
| CSU Criteria | Antihistamine-refractory, requiring biologics |
| Risk Assessment | 10-year cardiovascular risk (Framingham criteria) |
| Syndrome Evaluation | Metabolic syndrome (National Cholesterol Education Program) |
| Additional Metrics | Waist circumference, BMI, hypertension, CRP levels |
The analysis revealed a complex picture with both expected and unexpected discoveries. When comparing the CSU patient group against controls, researchers found significant differences in several important health parameters 1 .
| Parameter | CSU Patients | Control Subjects | P-value |
|---|---|---|---|
| Metabolic Syndrome Prevalence | Higher | Lower | <0.05 |
| Waist Circumference | Larger | Smaller | <0.05 |
| Body Mass Index (BMI) | Higher | Lower | <0.05 |
| Hypertension Incidence | More frequent | Less frequent | <0.05 |
| C-Reactive Protein (CRP) | Elevated | Normal range | <0.05 |
These findings confirmed that CSU patients showed a higher prevalence of factors comprising metabolic syndrome—a cluster of conditions that increase heart disease, stroke, and diabetes risk. The elevated CRP (C-reactive protein) in CSU patients was particularly noteworthy, as this marker indicates systemic inflammation and has been independently linked to cardiovascular risk in other populations 1 .
The most surprising finding emerged when researchers calculated the 10-year cardiovascular risk using the Framingham criteria. Despite the differences in individual risk factors, the overall risk scores did not show a statistically significant increase in CSU patients compared to controls. This suggests that while CSU patients may develop more cardiovascular risk factors, these may not have yet translated into significantly higher short-term cardiovascular risk 1 .
CSU patients showed significantly higher body mass index compared to controls
Increased waist circumference indicating central obesity in CSU patients
Higher C-reactive protein levels indicating systemic inflammation
Investigating the connection between chronic urticaria and cardiovascular health requires specialized methodologies and assessment tools. These are the key instruments and measures that enable researchers to quantify and analyze this complex relationship:
This widely used algorithm estimates an individual's 10-year likelihood of developing cardiovascular disease based on factors including age, sex, cholesterol levels, blood pressure, smoking status, and diabetes presence. Its validation in large population studies makes it invaluable for cardiovascular research 1 .
Defined by the National Cholesterol Education Program Adult Treatment Panel III, this diagnosis requires at least three of five components: elevated waist circumference, high triglycerides, reduced HDL cholesterol, elevated blood pressure, and high fasting glucose. Each component represents a distinct aspect of cardiovascular risk 1 .
The standardized tool for assessing urticaria severity tracks both hive count and itch intensity over seven days. This validated measure ensures consistent evaluation of treatment effectiveness across clinical studies 3 .
The management of antihistamine-refractory CSU has expanded dramatically in recent years, offering new hope for patients who previously had limited options. The current treatment approach follows a stepwise strategy 2 :
Second-generation H1 antihistamines at standard doses
Increasing antihistamine doses up to fourfold
Biological agents (omalizumab) or other immunomodulators
Omalizumab has demonstrated impressive results in clinical settings, with 34%-44% of patients achieving complete symptom control (UAS7=0) in phase 3 trials, and approximately two-thirds experiencing at least partial control 6 . The treatment works relatively quickly, with many patients noticing improvement within the first few weeks .
| Treatment | Mechanism | Stage of Development | Key Efficacy Findings |
|---|---|---|---|
| Dupilumab | Blocks IL-4 and IL-13 signaling (type 2 inflammation) | FDA-approved April 2025 | 13%-31% complete response at Week 24 6 |
| Remibrutinib | Oral Bruton's tyrosine kinase (BTK) inhibitor | Phase 3 trials completed | 28%-31% complete response at Week 12 2 |
| Barzolvolimab | Targets cKIT receptor, depleting mast cells | Phase 2 trials | High rates of UAS7=0; potential disease-modifying effect |
| Briquilimab | Monoclonal antibody targeting cKIT | Phase 2 evaluation | 100% of patients (3/3) achieved UAS7=0 in early cohort |
These emerging therapies are particularly exciting because they offer alternative mechanisms of action for patients who may not respond adequately to anti-IgE treatments. The oral administration route of remibrutinib also presents a convenience advantage over injectable biologics 2 .
Despite these advances, significant challenges remain. Studies indicate that approximately 60% of CSU patients are refractory to antihistamines, and 27-30% show minimal response to omalizumab . This persistent treatment gap continues to drive research into more effective and targeted therapies.
The Turkish cardiovascular risk study provides both reassurance and guidance for managing antihistamine-refractory CSU. The absence of significantly elevated 10-year cardiovascular risk suggests that biologic treatments like omalizumab don't appear to increase short-term cardiovascular danger. However, the increased prevalence of metabolic syndrome components—particularly hypertension, elevated waist circumference, and increased BMI—indicates that CSU patients should receive regular monitoring of these parameters 1 .
For patients living with antihistamine-refractory chronic urticaria, these findings underscore the importance of a comprehensive healthcare approach that addresses both skin symptoms and overall health. As one researcher noted, "Early diagnosis and treatment of metabolic syndrome and its components in these patients may play a role in preventing potential complications" 1 .
The journey to understand the full implications of chronic urticaria continues, but each study brings us closer to optimizing care for both the skin and the whole patient.